Ivermectin and malaria control

Abstract

As the world begins to realize the very real prospect of eliminating malaria as a public health problem globally, the scientific community is acutely aware that novel and innovative new tools will be required if that lofty goal is to be accomplished. Moreover, the need for comprehensive, integrated products and interventions is being recognized in order for the critical ‘final steps’ toward elimination to be taken successfully. Failure to take these crucial last steps have dogged all past global disease elimination programmes, except for smallpox. The success of ivermectin in driving two of the most devastating and disfiguring neglected tropical diseases (NTD) to the brink of elimination has been well documented. The drug also bestows immeasurable non-target benefits, increasing the health and socioeconomic prospects of all communities where mass drug administration (MDA) has been carried out. Ivermectin kills a variety of parasites and insects, including the Anopheline vectors of malaria parasites. In view of long-standing MDA programmes, increasing attention is now being paid to the potential offered by re-formulating and re-purposing ivermectin to function as a feed-though mosquitocidal tool. This will provide a comprehensively beneficial weapon, for the anti-malarial armamentarium, as well as for probably improving the impact on existing target diseases. Prospects currently look highly promising, especially as the drug is already proven to be extremely safe for human use. However, for maximum impact, detailed analysis of various analogues of the unique ivermectin, as well as the parent avermectin compounds, will need to be undertaken. ‘Ivermectin’ comprises an imprecise mix of two compounds, both of which are potent anthelmintics. Yet recently, it has been confirmed that only the minor of the two component compounds is molluscicidal. Further structure activity relationship studies may well identify the analogue, analogues or combination thereof best suited for use in a concerted initiative to simultaneously tackle malaria and other NTD in poly-parasitized communities.

Ivermectin Impairs the Development of Sexual and Asexual Stages of Plasmodium falciparumIn Vitro

“…Moreover, ivermectin availability was greater when the drug was administered in a hydroalcoholic solution, in comparison with a solid capsule formulation or a tablet (63). With the oral dose (400 g/kg) recommended by French authorities to control lymphatic filariasis (64), ivermectin plasma concentrations could reach up to 260 ng/ml when the drug was given with food, with a time to the maximal plasma concentration Ivermectin has a large volume of distribution (3.1 to 3.5 liters/kg) due to its high lipid solubility and its extensive protein binding (unbound fraction of Ͻ0.1), and the peak plasma concentration occurs approximately 4 h after oral dosing, with a second peak at 6 to 12 h, probably arising due to enterohepatic recycling, and a plasma half-life of ϳ12 h (60,65,66). A recent study investigating the malaria-transmissionblocking potential of ivermectin used concentrations of 300 g/kg or 600 g/kg given on 3 consecutive days (total dose of 900 g/kg or 1,800 g/kg, respectively) in a fasted state, reaching plasma concentrations of around 69.4 ng/ml (range, 34.1 to 196.3 ng/ml) or 118.9 ng/ml (range, 45.2 to 455.1 ng/ml), respectively, and showed that these doses were well tolerated and reduced mosquito survival rates for at least 28 days after treatment (67,68).…”

On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes

“…The most used endectocide drug (it has activity against endo- and ectoparasites when applied to the host) in human and livestock is Ivermectin, capable of killing a wide variety of parasites and vectors [42,43]. It targets a broad range of parasites and invertebrates, including mosquitoes [44–47], and it has been proposed as an additional tool to control vector-borne diseases such as malaria [48–54].…”

Newer Approaches for Malaria Vector Control and Challenges of Outdoor Transmission

“…Another approach for controlling mosquitoes is based on endectocide ivermectin, a molecule that has been used for more than 30 years to control lymphatic filariasis. This molecule remains in the human bloodstream following a standard oral dose and can kill Anopheles mosquitoes that feed on the blood of medicated persons [76][77][78][79]. Controlling vector mosquito populations is a difficult task and so the addition of new technologies to be considered for IVM will help improve the effectiveness of vector-borne disease transmission [80][81][82][83].…”

“…The most important topics to be considered that are also in agreement with the WHO criteria, comprise: (1) assessment of the health system limitations to improve processes and methods aiming for the improvement in efficacy of vector control; (2) implementation of mosquito surveillance for the development of guidelines and models of the risk of disease transmission ( Figure 3); (3) development of effective and environmentally friendly strategies to reduce malaria and other vector-borne disease transmission, following the recommendations by VCAG and considering the increase of insecticide resistance [100,102]. To our understanding, traditional insecticide-based control efforts, such as IRS and LLIN, should be used in combination with novel eco-friendly tools, such as "eave tubes technology," ATSB methods, and even the employment of the ectendocide ivermectin [40,44,76]. These new mosquito control tools should be accompanied by (4) an evaluation of their effectiveness, assessment of their usefulness and impact through randomized controlled trials with entomological and epidemiological outcomes (Figure 3), this has been done for traditional control strategies such as LLINs and IRS; (5) the monitoring of man-made alteration in the environment and its impact in the dynamics of malaria vectors; and (6) the establishment of a multi-disciplinary team with different areas of expertise (Figure 3) [100,102,120].…”